Department of Cancer Biology; Department of Molecular Genetics and Microbiology
Adenocarcinoma; Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; *DNA Damage; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; Prostatic Neoplasms; Protein-Serine-Threonine Kinases; RNA, Small Interfering; Transfection; Transplantation, Heterologous
Cancer Biology | Microbiology | Molecular Genetics
Tumor cells often become resistant to DNA damage-based therapy; however, the underlying mechanisms are not yet understood. Here, we show that tumor cells exposed to DNA damage counteract cell death by releasing the antiapoptotic protein, survivin, from mitochondria. This is independent of p53, and requires activated checkpoint kinase 2 (Chk2), a putative tumor suppressor. Molecular or genetic targeting of Chk2 prevents the release of survivin from mitochondria, enhances DNA damage-induced tumor cell apoptosis, and inhibits the growth of resistant in vivo tumors. Therefore, activated Chk2 circumvents its own tumor-suppressive functions by promoting tumor cell survival. Inhibiting Chk2 in combination with DNA-damaging agents may provide a rational approach for treating resistant tumors.
DOI of Published Version
Cancer Res. 2006 Dec 15;66(24):11576-9. Link to article on publisher's site
Ghosh JC, Dohi T, Raskett CM, Kowalik TF, Altieri DC. (2006). Activated checkpoint kinase 2 provides a survival signal for tumor cells. Open Access Articles. https://doi.org/10.1158/0008-5472.CAN-06-3095. Retrieved from https://escholarship.umassmed.edu/oapubs/343